The main objective of this proposal is to determine the viral genetic determinants involved in tissue-specific tumor induction in the mouse by polyoma virus. This will be done by in vitro construction of recombinant viral genomes, involving two "wild type" parental virus strains which differ strongly in their oncogenicity in the natural host. One strain induces only mesenchymal tumors, and only at a low efficiency and after a long latent period. The other strain rapidly and efficiently induces tumors of epithelial origin. Cloned parental viral DNAs are used to generate recombinants containing various combinations of structural or regulatory (enhancer) sequences from the parents. The recombinants are then assayed by injection into newborn mice and histopathological studies. Virus mutants with structural mutations in the T antigen coding early region will also be studied for their ability to induce tumors at various sites, as well as to replicate and establish persistent infections.